Maternal transmission of HlV-1 is a growing problem worldwide. We will test two key issues in congenital HIV-1 infection in primate models: the mechanism of neonatal infection across intact mucosa, and the fate of mucosal Langerhans cells (LC) during disease progression. Our group is uniquely qualified to conduct this work. First, by inoculating simian immunodeficiency virus (SlV) into amniotic fluid, we created a primate model for in utero infection. Second, by exposing neonatal macaques orally to SIV following C-section, we created a primate model which mimics intrapartum mucosal transmission. For both models, high infection rates were achieved. Using oral infection at birth with SIVdelta3, which is deleted in nef, vpr and NRE, and which is attenuated in adult macaques after intravenous (i.v.) infection, we made a startling finding: SIVdelta3 replicated to high levels and caused AIDS in infants. This led us to hypothesize that a) mucosal LC play a pivotal role in the early dissemination of SlV across neonatal mucosal surfaces; b) that these steps require neither Nef nor Vpr; and c) that infection of LC may play a key role in the pathogenesis of primate immunodeficiency virus infection in neonates. The Specific Aims are to: 1. Compare the susceptibility of cultured neonatal LC to lentiviral infection with that of adult cells and investigate the mechanism(s) of virus dissemination from acutely infected LC; compare the rate of virus production by LC exposed to isogenic HIV-1 and SIV differing only in nef or vpr. 2. Determine the portal of virus entry (using wild-type SIVmac251) initial target cells and pattern of virus spread following oral or i.v. infection of neonates. Are IC the earliest cells infected after oral infection? Do LC, and dendritic cells in general, undergo apoptosis in infected neonates? 3. Determine the infection rate and fate of LC during the clinically asymptomatic period after seroconversion following oral or i.v. neonatal infection, and after full-blown AIDS has developed. 4. Determine infection rate and fate of LC after in utero infection; test whether viral load, number or phenotype of apoptotic cells, or the rate of disease progression differ in neonates infected before and after acquiring the capability to mount immune responses. 5. Test whether immune activation precipitates wide-spread apoptosis in SIV-infected infant macaques. Are LC, and dendritic cells in general, lost as a consequence? The proposed work, which is based on our prior accomplishments, is highly significant because it will yield new insights into lentiviral pathogenesis during ontogeny.